IMFAR – IES: Imaging Genetics in ASD

The author is a guest blogger, Ashley Scott-Van Zeeland, Ph.D. and she is a Dickenson Fellow at the Scripps Translational Science Institute in La Jolla.

This was the second year IMFAR hosted an Invited Educational Symposium on Imaging Genetics in autism spectrum disorders. Dr. Susan Bookheimer, a leader in brain imaging and one of the pioneers of imaging genetics, and Dr. Daniel Geschwind a world-renowned autism geneticist, chaired the session. The goals of the symposium were to introduce the principles behind imaging genetics and demonstrate methods by which various researchers are using imaging genetics to discover relationships between genetics and brain function.

The first speaker was Dr. Susan Bookheimer, Professor of Cognitive Neurosciences from UCLA. Dr. Bookheimer gave a broad overview of the use of brain images as quantitative measures for use in imaging genetics investigations. Essentially, neural measurements such as activation or metabolic response, structural volumes, or connectivity measures can be thought of as being one step closer to the mechanism of gene action than broad diagnostic classifications. Therefore, these types of ‘endophenotypes’ are more strongly associated with gene variants and should considerably increase the ability to identify brain-gene relationships.

Dr. Daniel Geschwind, Chair of Human Genetics and Professor of Neurology at UCLA followed with a general primer on genetics to introduce all clinicians, brain imagers, and non-geneticists to the types of genetic assays available. The goal of Dr. Geschwind’s talk was to encourage non-geneticists to consider what is “reasonable” from a genetics perspective when designing studies. He highlighted three main frameworks for imaging genetics studies: 1) Identify genetic factors that underlie normal brain structural and/or functional variation 2) use differences in brain imaging measures to identify disease-associated genes, or 3) use brain imaging as a way understand the neurobiological effects and neural mechanisms of disease-associated genes. He also re-emphasized the issue of statistical power in the search for disease-associated genes, which depends on many factors but can be increased by using brain imaging that likely has larger detectable gene effects than broader phenotypes such as autism diagnosis. He also stressed that the best imaging genetic approaches are hypothesis driven, with known implicated brain regions or neural effects to limit statistical issues caused by testing many genetic markers over many brain regions.

After the introductory talks by Drs. Bookheimer and Geschwind, there were three more talks that went into greater detail about current applications of imaging genetic approaches in the study of autism – the first being by Dr. Joshua Trachtenberg, Assistant Professor of Neurobiology at UCLA. Dr. Trachtenberg presented methods for imaging dendritic growth in animal models. Using cutting edge 2-photon microscopy techniques, Dr. Trachtenberg is able to examine the neurobiological effects of candidate autism risk genes in a living animal. His lab has been working on the PTEN gene, which has been associated with an enlarged brain. In order to determine how PTEN contributes to an enlarged brain, Dr. Trachtenberg is able to selectively alter the PTEN gene in mouse brain after birth and monitor the changes in neural architecture over time. In the PTEN mutant animals, Dr. Trachtenberg observed up to 50% extra growth of dendrites – neuronal structures that receive input from other cells – suggesting a mechanism by which this autism-associated gene contributes to larger brain size. Importantly, he also presented evidence that the dendrites involved in long-range communication circuits are more affected than those involved in short-range circuits – a story that is emerging as a consistent finding across many measures of brain connectivity in autism.

Next, Dr. Declan Murphy, Professor of Psychiatry and Brain Maturation and the Head of Department of Forensic and Neurodevelopmental Science at Kings College in London presented an overview of the state of the field for serotonin genes and imaging genetics. Serotonin is a neurotransmitter involved in both brain function and brain development, and has been associated with behaviors such as aggression, affiliative behaviors, and obsessional behaviors. There are two major serotonin genes that have been the focus of imaging genetics studies – MAOA and 5-HTTLPR. MAOA is involved in the breakdown of serotonin and 5-HTTLPR encodes a protein that transports serotonin into neurons. Both genes have been associated with many neuropsychiatric disorders, including autism. Dr. Murphy presented studies in which activity in the amygdala and fusiform gyrus, regions thought to play a role in autism, was associated with different versions of 5-HTTLPR. However, he noted that although there is some evidence for serotonin dysfunction in autism, the evidence is not conclusive and imaging studies reflect this as well. In structural MRI studies, investigators have found frontal lobe abnormalities associated with the serotonin transporter, though this has not consistently been replicated. Within this talk, Dr. Murphy emphasized that it remains important to search beyond simple gene effects and consider systems-based approaches, developmental effects, gene-gene interactions and pharmacogenetic effects in imaging genetics studies.

I had the great pleasure of wrapping up the session by describing a general framework for pursuing targeted imaging genetics studies in autism, using a recent study that explored frontal lobe connectivity and an autism risk gene, CNTNAP2. As imaging genetics studies can be quite difficult, it is important to begin with well-devised experimental paradigms and testable hypotheses for gene effects. Since CNTNAP2 encodes a protein that is involved in cell-cell interactions and synaptic transmission, we reasoned that CNTNAP2 might be related to neural connectivity. As mentioned by Dr. Bookheimer in the introduction, it is important to use brain imaging as a quantitative measure of brain function or structure. To this end we chose to use a functional paradigm that we knew would elicit activity in regions where CNTNAP2 is expressed during development. We observed differences in frontal lobe activity in both typical children and those with autism depending on which CNTNAP2 allele they carried, and also found differences in connectivity patterns with the frontal lobe such that children who carried the autism-associated risk gene had more local frontal connections and reduced long-range connections. In sum, by leveraging information about the role of CNTNAP2 in the brain , we were able to better understand the mechanism by which CNTNAP2 contributes to increased risk for autism using an imaging genetics approach.

Overall, the application of imaging genetics to autism spectrum disorders is beginning to reveal very interesting neurobiology and I expect we will see more of these types of studies at IMFAR 2012!

The CNTNAP2 gene variant is found in 1/3rd of the general population. It is associated with intellectual disability, epilepsy, developmental language disorders and sometimes with co-occurring autism. In most cases the common genetic variant is associated with normal developemnt as would be expected with a genetic variant that occurs in 1/3rd of the general population. The author of this post needs to understand she is communicating with parents and genetic studies should be required to publish the relative risk for autism, with respect to the CNTNAP2 gene, the relative risk is very small and the risk is not specific to autism but represents a small risk for an early disruption of brain developmental and a broad spectrum of neurodevelopmental and neuropsychiatric disorders.

Please help my 39 year old son who cycle has severe meltdowns at least every 3 months. In placement thats especially mentally abusive . All untrained staff. They had him arrested for breaking a plastic cup , kicked officer while being restrained now on PROBATION if any more incidents and he will have them for sure. Marsha Duty. Jrduty

I understand this is all very interesting and exciting to researchers and academics but to families of children living today with autism the endless, absolutely endless and hugely expensive brian imaging projects have a high cost/ low yield ratio. Moreover, it illustrates the Grand Canyon like gulf between research families desperately want funded vs. research academics find interesting.

IMFAR academics need to attend an NAA, ARI or AutismOne conference and learn more about the community they need to serve.

You know how many published studies there are on autism and brain imaging- 953!

Guess how many published studies on autism and the immune system – 253. The immune system is the lynchpin of the biological aspects of ASD. For parents of medically affected kids – our best medical tool is the internet. Meanwhile hundreds of millions of dollars are been spent to describe what we already know about ASD and the brain. Autism is brian inflammation.
We can measure the brain 1,000x different ways and all we do is describe the accident after the fact.
We know our children have traumatic brain injuries – it is time to rigorously study the likely environmental triggers – and stop this inane focus of the brain in isolation. We just cannot afford this.

Let us focus on ways to prevent and treat autism – rather than keep making empty promises that “someday” the identification of pathways will somehow facilitate drugs. I am not holding my breath. Meanwhile try helping us treat GI disease, stop and reverse regression, studying ivig, TSO, the effects of AL (which has replaced) Hg in vaccines on the developing neurological system.

You know what saved us was CT scans that clearly showed the blockages. Our ENT performed the miracle that saved my child’s life. After four surgeries to remove the infection and repair the sinus area, my son can finally see (eye contact), hear (language repaired), feel (inflammation removed), taste (strep bacteria gone), and touch (stress and nerves relieved from the swelling). The relief has allowed his intestines to repair and he has steadily regained strength throughout his body. He can smile without the pain. He went from an isolation room at school to regular classes without an assistant. He is listed in the yearbook as “Funniest Laugh”!
You are so right Ms. Wright! If the poor psychiatrists would only take a class in biology and understand what inflammation and infections can do to a child during the development of critical sensory connections. Pain is the reason that so many children have aggression and obsessional behaviors. I know common sense research is not as attractive as imaging genetic profiles, but why not acknowledge the presence of the physical, measurable, and evident issues such as allergies, inflammation, infection, and respiration issues that are causing pain in children. These issues should be treated in children regardless of what psychologists continue to theorize about “autism”.

Janice I am so thrilled for your family!
What a terrific ENT you have for picking that up.
Allergies are essentially inflammation that all too often go untreated- leading to pain.
My son was self- abusive until we found the right allergy meds. Finding the right, specially made
inhaler- with NO preservatives was very difficult.
PANDAS was and is a re-occuring nightmare for my son. It kept him in and out of hospitals for yrs.
You are pretty much on your own as parents to figure this out.
More brain imaging research is the last thing our families need.

Yes, I have taken information about PANDAS to doctors for years only for them to pat me on the back and offer the traditional off-label prescription advise. Even the largest children’s hospital in our area dismissed PANDAS, and yes brain imaging and genetic proselytizing are big priorities ahead of simple allergy relief or the correct antibiotic for strep.
Our families need doctors to acknowledge that children with chronic illness, frequent infections, diarrhea, constipation, inflammation and the resulting “emotional roller coaster” are not simply healthy children with an altered gene(s) somewhere. (Aren’t they up to 100 or more genes now)
Thank goodness for the professionals that are willing to help with successful medical treatments despite the lack of genomic awareness in the medical community.